Hepatic Expression of Thyroid Hormone-Responsive Spot 14 Protein Is Regulated by Constitutive Androstane Receptor (NR1I3)

Abstract

The pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR) were initially isolated as nuclear receptors regulating xenobiotic metabolism and elimination, alleviating chemical insults. However, recent works suggest that these xenoreceptors play an endobiotic role in modulating hepatic lipid metabolism. In this study, we show that CAR activators]phenobarbital and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] induce the lipogenic gene thyroid hormone-responsive spot 14 protein (THRSP) (or Spot14, S14) expression in human hepatocytes. In addition, we report that treatment of wild-type mice with mCAR activators (phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene) efficiently increases thrsp expression, in contrast to CAR null mice. We demonstrate that CAR directly transactivates THRSP promoter through the direct repeat with 4-bp spacer thyroid hormone and PXR response element. Deletion or point mutations within this PXR response element led to a drastic inhibition of CAR-mediated THRSP transactivation. Gel-shift analysis revealed that the CAR/retinoid X receptor complex binds to this element. In conclusion, our results indicate that THRSP gene is a CAR and PXR target gene. Because THRSP expression correlates with lipogenesis and insulin sensitivity, our data suggest that CAR and/or PXR activating drugs and xenobiotics may promote aberrant hepatic de novo lipogenesis leading potentially to fatty liver diseases and insulin resistance.

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

“…In vitro data from the hepatic Huh7 cell line and cryopreserved small hepatocytes have shown that TH may regulate the expression of specific CAR target genes possibly by binding of the activated TH receptor to the PBREM region (Ooe et al 2009, Bing et al 2014. In addition, it was shown that CAR itself can regulate the TH responsive gene Thrsp through binding to TRE sequences of the promoter region (Breuker et al 2010). Since xenobiotics are known to exert strong influence on TH metabolism, it is important to consider that activation of CAR by 3,5-T 2 might alter hepatic TH homeostasis via secondary mechanisms through induced liver DME synthesis and enhanced TH clearance (Maglich et al 2004, Qatanani et al 2005, Radovic et al 2010, Roques et al 2013, Schraplau et al 2014.…”

Impact of Inflammation on Chlorpromazine-Induced Cytotoxicity and Cholestatic Features in HepaRG Cells

“…In agreement with morphologic observations, overexpression of ADFP, PLIN4, SCD1, LPIN1 was not prevented by cotreatment with either cytokine, suggesting that an inflammation stress does not affect induction of phospholipidosis by CPZ. It is noteworthy that expression of the PXR/ CAR target gene THRSP was down-regulated by cytokines, especially IL-6, as a consequence of their ability to down-regulate these nuclear receptors (Breuker et al, 2010). At 50 mM, CPZ was found to generate an early oxidative stress, which was associated with an inhibition of TA efflux, and shortly later, of its uptake, and alterations of bile canaliculi structures (Antherieu et al, 2013).…”

Polymorphism identification in the goat <i>THRSP</i> gene and association analysis with growth traits

“…The messenger RNA expression of THRSP was highly correlated with intramuscular fat content of an individual in Wagyu × Hereford cattle (Wang et al 2009). Research showed that the THRSP gene has impact on chicken fat metabolism (Breuker et al 2010) and SNPs could be used in molecular marker assistant selection (MAS) as a genetic marker for the chicken and pig growth traits (Wang et al 2004, d'Andre Hirwa et al 2010. However, up to now, the research about SNPs of the THRSP gene was not reported in goat.…”